Bisphenol ether derivatives and methods for using the same

ABSTRACT

Compounds having a structure of Formula I, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1, R2, L1, L2, L3, X, a, b, c, n, and m are as defined herein, are provided. Uses of such compounds for modulating androgen receptor activity and uses as therapeutics as well as methods for treatment of subjects in need thereof, including prostate cancer are also provided.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation application of U.S. application Ser.No. 15/557,726, filed Sep. 12, 2017, which is a U.S. National StageApplication under 35 U.S.C. § 371 of International Patent ApplicationNo. PCT/CA2016/000070, filed Mar. 11, 2016, which claims priority toU.S. Provisional Application No. 62/131,969 filed Mar. 12, 2015, thedisclosures of which are herein incorporated by reference in theirentirety for all purposes.

STATEMENT OF GOVERNMENT INTEREST

This invention was made in part with government support under Grant No.2R01 CA105304 awarded by the National Cancer Institute. The UnitedStates Government has certain rights in this invention.

BACKGROUND Technical Field

This invention generally relates to bisphenol-related compounds andtheir use for treatment of various indications. In particular theinvention relates to bisphenol ether compounds having a chlorohydrin ora protected chlorohydrin moiety and their use for treatment of variouscancers, for example all stages of prostate cancer, including androgendependent, androgen sensitive and castration-resistant prostate cancers.This invention also relates to bisphenol-related compounds and their usefor modulating androgen receptor (AR) activity.

Description of the Related Art

Androgens mediate their effects through the androgen receptor (AR).Androgens play a role in a wide range of developmental and physiologicalresponses and are involved in male sexual differentiation, maintenanceof spermatogenesis, and male gonadotropin regulation (R. K. Ross, G. A.Coetzee, C. L. Pearce, J. K. Reichardt, P. Bretsky, L. N. Kolonel, B. E.Henderson, E. Lander, D. Altshuler & G. Daley, Eur Urol 35, 355-361(1999); A. A. Thomson, Reproduction 121, 187-195 (2001); N. Tanji, K.Aoki & M. Yokoyama, Arch Androl 47, 1-7 (2001)). Several lines ofevidence show that androgens are associated with the development ofprostate carcinogenesis. Firstly, androgens induce prostaticcarcinogenesis in rodent models (R. L. Noble, Cancer Res 37, 1929-1933(1977); R. L. Noble, Oncology 34, 138-141 (1977)) and men receivingandrogens in the form of anabolic steroids have a higher incidence ofprostate cancer (J. T. Roberts & D. M. Essenhigh, Lancet 2, 742 (1986);J. A. Jackson, J. Waxman & A. M. Spiekerman, Arch Intern Med 149,2365-2366 (1989); P. D. Guinan, W. Sadoughi, H. Alsheik, R. J. Ablin, D.Alrenga & I. M. Bush, Am J Surg 131, 599-600 (1976)). Secondly, prostatecancer does not develop if humans or dogs are castrated before puberty(J. D. Wilson & C. Roehrborn, J Clin Endocrinol Metab 84, 4324-4331(1999); G. Wilding, Cancer Surv 14, 113-130 (1992)). Castration of adultmales causes involution of the prostate and apoptosis of prostaticepithelium while eliciting no effect on other male external genitalia(E. M. Bruckheimer & N. Kyprianou, Cell Tissue Res 301, 153-162 (2000);J. T. Isaacs, Prostate 5, 545-557 (1984)). This dependency on androgensprovides the underlying rationale for treating prostate cancer withchemical or surgical castration (androgen ablation).

Androgens also play a role in female diseases such as polycystic ovarysyndrome as well as cancers. One example is ovarian cancer whereelevated levels of androgens are associated with an increased risk ofdeveloping ovarian cancer (K. J. Helzlsouer, A. J. Alberg, G. B. Gordon,C. Longcope, T. L. Bush, S. C. Hoffman & G. W. Comstock, JAMA 274,1926-1930 (1995); R. J. Edmondson, J. M. Monaghan & B. R. Davies, Br JCancer 86, 879-885 (2002)). The AR has been detected in a majority ofovarian cancers (H. A. Risch, J Natl Cancer Inst 90, 1774-1786 (1998);B. R. Rao & B. J. Slotman, Endocr Rev 12, 14-26 (1991); G. M. Clinton &W. Hua, Crit Rev Oncol Hematol 25, 1-9 (1997)), whereas estrogenreceptor-alpha (ERa) and the progesterone receptor are detected in lessthan 50% of ovarian tumors.

The only effective treatment available for advanced prostate cancer isthe withdrawal of androgens which are essential for the survival ofprostate epithelial cells. Androgen ablation therapy causes a temporaryreduction in tumor burden concomitant with a decrease in serumprostate-specific antigen (PSA). Unfortunately prostate cancer caneventually grow again in the absence of testicular androgens(castration-resistant disease) (Huber et al 1987 Scand J. Urol Nephrol.104, 33-39). Castration-resistant prostate cancer is biochemicallycharacterized before the onset of symptoms by a rising titre of serumPSA (Miller et al 1992 J. Urol. 147, 956-961). Once the disease becomescastration-resistant most patients succumb to their disease within twoyears.

The AR has distinct functional domains that include the carboxy-terminalligand-binding domain (LBD), a DNA-binding domain (DBD) comprising twozinc finger motifs, and an N-terminus domain (NTD) that contains one ormore transcriptional activation domains. Binding of androgen (ligand) tothe LBD of the AR results in its activation such that the receptor caneffectively bind to its specific DNA consensus site, termed the androgenresponse element (ARE), on the promoter and enhancer regions of“normally” androgen regulated genes, such as PSA, to initiatetranscription. The AR can be activated in the absence of androgen bystimulation of the cAMP-dependent protein kinase (PKA) pathway, withinterleukin-6 (IL-6) and by various growth factors (Culig et al 1994Cancer Res. 54, 5474-5478; Nazareth et al 1996 J. Biol. Chem. 271,19900-19907; Sadar 1999 J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 AJ. Biol. Chem. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277,38087-38094). The mechanism of ligand-independent transformation of theAR has been shown to involve: 1) increased nuclear AR protein suggestingnuclear translocation; 2) increased AR/ARE complex formation; and 3) theAR-NTD (Sadar 1999 J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 A J.Biol. Chem. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277,38087-38094). The AR may be activated in the absence of testicularandrogens by alternative signal transduction pathways incastration-resistant disease, which is consistent with the finding thatnuclear AR protein is present in secondary prostate cancer tumors (Kimet al 2002 Am. J. Pathol. 160, 219-226; and van der Kwast et al 1991Inter. J. Cancer 48, 189-193).

Available inhibitors of the AR include nonsteroidal antiandrogens suchas bicalutamide (Casodex™), nilutamide, flutamide, enzulutamide andinvestigational drug ARN-509 and steroidal antiandrogens, such ascyproterone acetate. These antiandrogens target the LBD of the AR andpredominantly fail presumably due to poor affinity and mutations thatlead to activation of the AR by these same antiandrogens (Taplin, M. E.,Bubley, G. J., Kom Y. J., Small E. J., Uptonm M., Rajeshkumarm B., BalkmS. P., Cancer Res., 59, 2511-2515 (1999)). These antiandrogens wouldalso have no effect on the recently discovered AR splice variants thatlack the ligand-binding domain (LBD) to result in a constitutivelyactive receptor which promotes progression of castration recurrentprostate cancer (Dehm S M, Schmidt L J, Heemers H V, Vessella R L,Tindall D J., Cancer Res 68, 5469-77, 2008; Guo Z, Yang X, Sun F, JiangR, Linn D E, Chen H, Chen H, Kong X, Melamed J, Tepper C G, Kung H J,Brodie A M, Edwards J, Qiu Y., Cancer Res. 69, 2305-13, 2009; Hu et al2009 Cancer Res. 69, 16-22; Sun et al 2010 J Clin Invest. 2010 120,2715-30).

Conventional therapy has concentrated on androgen-dependent activationof the AR through its C-terminal domain. Studies developing antagoniststo the AR have concentrated on the C-terminus and specifically: 1) theallosteric pocket and AF-2 activity (Estébanez-Perpiñá et al 2007, PNAS104, 16074-16079); 2) in silico “drug repurposing” procedure foridentification of nonsteroidal antagonists (Bisson et al 2007, PNAS 104,11927-11932); and coactivator or corepressor interactions (Chang et al2005, Mol Endocrinology 19, 2478-2490; Hur et al 2004, PLoS Biol 2,E274; Estébanez-Perpiñá et al 2005, JBC 280, 8060-8068; He et al 2004,Mol Cell 16, 425-438).

The AR-NTD is also a target for drug development (e.g. WO 2000/001813),since the NTD contains Activation-Function-1 (AF-1) which is theessential region required for AR transcriptional activity (Jenster et al1991. Mol Endocrinol. 5, 1396-404). The AR-NTD importantly plays a rolein activation of the AR in the absence of androgens (Sadar, M. D. 1999J. Biol. Chem. 274, 7777-7783; Sadar M D et al 1999 Endocr Relat Cancer.6, 487-502; Ueda et al 2002 J. Biol. Chem. 277, 7076-7085; Ueda 2002 J.Biol. Chem. 277, 38087-38094; Blaszczyk et al 2004 Clin Cancer Res. 10,1860-9; Dehm et al 2006 J. Biol Chem. 28, 27882-93; Gregory et al 2004 JBiol Chem. 279, 7119-30). The AR-NTD is important in hormonalprogression of prostate cancer as shown by application of decoymolecules (Quayle et al 2007, Proc Natl Acad Sci USA. 104,1331-1336).

While the crystal structure has been resolved for the AR C-terminus LBD,this has not been the case for the NTD due to its high flexibility andintrinsic disorder in solution (Reid et al 2002 J. Biol. Chem. 277,20079-20086) thereby hampering virtual docking drug discoveryapproaches. Compounds that modulate AR include the bis-phenol compoundsdisclosed in published PCT Nos: WO 2010/000066, WO 2011/082487; WO2011/082488; WO 2012/145330; WO 2012/139039; WO 2012/145328; WO2013/028572; WO 2013/028791; WO 2014/179867 and WO 2015/031984,which arehereby incorporated by reference in their entireties, to the BritishColumbia Cancer Agency Branch and The University of British Columbia.

BRIEF SUMMARY

The present disclosure is based in part on the discovery that thecompounds described herein, may be used to modulate AR activity eitherin vivo or in vitro for both research and therapeutic uses. Inaccordance with one embodiment, there is provided a compound having astructure of Formula I:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein R¹, R², L¹, L², L³, X, a, b, c, n, and m are as defined herein,are provided.

In other embodiments pharmaceutical compositions comprising a compoundof Formula I are provided. Methods for modulating AR activity employingthe present compounds and pharmaceutical compositions are also provided.

These and other aspects of the invention will be apparent upon referenceto the following detailed description. To this end, various referencesare set forth herein which describe in more detail certain backgroundinformation, procedures, compounds and/or compositions, and are eachhereby incorporated by reference in their entirety.

BRIEF DESCRIPTION OF THE DRAWINGS

In the figures, identical reference numbers identify similar elements.The sizes and relative positions of elements in the figures are notnecessarily drawn to scale and some of these elements are arbitrarilyenlarged and positioned to improve figure legibility. Further, theparticular shapes of the elements as drawn are not intended to conveyany information regarding the actual shape of the particular elements,and have been solely selected for ease of recognition in the figures.

FIGS. 1A and 1B shows the ¹H NMR (nuclear magnetic resonancespectroscopy) and the ¹³C NMR spectra for Compound 1a, respectively.

FIG. 2 shows the ¹³C NMR spectrum for(S)-4-((4-(2-(4-((S)-2-chloro-3-(triphenyl-l4-oxidanyl)propoxy)phenyl)propan-2-yl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxolane.

FIGS. 3A and 3B shows the ¹H NMR and the ¹³C NMR spectra for(S)-1-(4-(2-(4-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)-3-(triphenyl-l4-oxidanyl)propan-2-ol,respectively.

FIGS. 4A and 4B shows the ¹H NMR and the ¹³C NMR spectra for(R)-3-(4-(2-(4-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol,respectively.

FIGS. 5A and 5B shows the ¹H NMR and the ¹³C NMR spectra for Compound1c, respectively.

DETAILED DESCRIPTION I. Definitions

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention maybe practiced without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed invention.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment. Thus, the appearances of the phrases “in one embodiment” or“in an embodiment” in various places throughout this specification arenot necessarily all referring to the same embodiment. Furthermore, theparticular features, structures, or characteristics may be combined inany suitable manner in one or more embodiments. Also, as used in thisspecification and the appended claims, the singular forms “a,” “an,” and“the” include plural referents unless the content clearly dictatesotherwise. It should also be noted that the term “or” is generallyemployed in its sense including “and/or” unless the content clearlydictates otherwise.

The terms below, as used herein, have the following meanings, unlessindicated otherwise:

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo radical.“Halo” or “halogen” can also refer to radioactive isotopes of theelements listed above, e.g., ¹²³I and ¹⁸F.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Imino” refers to the ═NH substituent.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” or “alkyl group” refers to a fully saturated, straight orbranched hydrocarbon chain radical having from one to twelve carbonatoms, and which is attached to the rest of the molecule by a singlebond. Alkyls comprising any number of carbon atoms from 1 to 12 areincluded. An alkyl comprising up to 12 carbon atoms is a C₁-C₁₂ alkyl,an alkyl comprising up to 10 carbon atoms is a C₁-C₁₀ alkyl, an alkylcomprising up to 6 carbon atoms is a C₁-C₆ alkyl and an alkyl comprisingup to 5 carbon atoms is a C₁-C₅ alkyl. A C₁-C₅ alkyl includes C₅ alkyls,C₄ alkyls, C₃ alkyls, C₂ alkyls and C₁ alkyl (i.e., methyl). A C₁-C₆alkyl includes all moieties described above for C₁-C₅ alkyls but alsoincludes C₆ alkyls. A C₁-C₁₀ alkyl includes all moieties described abovefor C₁-C₅ alkyls and C₁-C₆ alkyls, but also includes C₇, C₈, C₉ and C₁₀alkyls. Similarly, a C₁-C₁₂ alkyl includes all the foregoing moieties,but also includes C₁₁ and C₁₂ alkyls. Non-limiting examples of C₁-C₁₂alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl,i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwisespecifically in the specification, an alkyl group can be optionallysubstituted.

“Alkylene” or “alkylene chain” refers to a fully saturated, straight orbranched divalent hydrocarbon chain radical, and having from one totwelve carbon atoms. Non-limiting examples of C₁-C₁₂ alkylene includemethylene, ethylene, propylene, n-butylene, ethenylene, propenylene,n-butenylene, propynylene, n-butynylene, and the like. The alkylenechain is attached to the rest of the molecule through a single bond andto the radical group through a single bond. The points of attachment ofthe alkylene chain to the rest of the molecule and to the radical groupcan be through one carbon or any two carbons within the chain. Unlessstated otherwise specifically in the specification, an alkylene chaincan be optionally substituted.

“Alkenyl” or “alkenyl group” refers to a straight or branchedhydrocarbon chain radical having from two to twelve carbon atoms, andhaving one or more carbon-carbon double bonds. Each alkenyl group isattached to the rest of the molecule by a single bond. Alkenyl groupcomprising any number of carbon atoms from 2 to 12 are included. Analkenyl group comprising up to 12 carbon atoms is a C₂-C₁₂ alkenyl, analkenyl comprising up to 10 carbon atoms is a C₂-C₁₀ alkenyl, an alkenylgroup comprising up to 6 carbon atoms is a C₂-C₆ alkenyl and an alkenylcomprising up to 5 carbon atoms is a C₂-C₅ alkenyl. A C₂-C₅ alkenylincludes C₅ alkenyls, C₄ alkenyls, C₃ alkenyls, and C₂ alkenyls. A C₂-C₆alkenyl includes all moieties described above for C₂-C₅ alkenyls butalso includes C₆ alkenyls. A C₂-C₁₀ alkenyl includes all moietiesdescribed above for C₂-C₅ alkenyls and C₂-C₆ alkenyls, but also includesC₇, C₈, C₉ and C₁₀ alkenyls. Similarly, a C₂-C₁₂ alkenyl includes allthe foregoing moieties, but also includes C₁₁ and C₁₂ alkenyls.Non-limiting examples of C₂-C₁₂ alkenyl include ethenyl (vinyl),1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl,1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl,7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl,6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl,4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl,1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl,6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl,1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl,6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and11-dodecenyl. Unless stated otherwise specifically in the specification,an alkyl group can be optionally substituted.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain radical, having from two to twelve carbonatoms, and having one or more carbon-carbon double bonds. Non-limitingexamples of C₂-C₁₂ alkenylene include ethene, propene, butene, and thelike. The alkenylene chain is attached to the rest of the moleculethrough a single bond and to the radical group through a single bond.The points of attachment of the alkenylene chain to the rest of themolecule and to the radical group can be through one carbon or any twocarbons within the chain. Unless stated otherwise specifically in thespecification, an alkenylene chain can be optionally substituted.

“Alkynyl” or “alkynyl group” refers to a straight or branchedhydrocarbon chain radical having from two to twelve carbon atoms, andhaving one or more carbon-carbon triple bonds. Each alkynyl group isattached to the rest of the molecule by a single bond. Alkynyl groupcomprising any number of carbon atoms from 2 to 12 are included. Analkynyl group comprising up to 12 carbon atoms is a C₂-C₁₂ alkynyl, analkynyl comprising up to 10 carbon atoms is a C₂-C₁₀ alkynyl, an alkynylgroup comprising up to 6 carbon atoms is a C₂-C₆ alkynyl and an alkynylcomprising up to 5 carbon atoms is a C₂-C₅ alkynyl. A C₂-C₅ alkynylincludes C₅ alkynyls, C₄ alkynyls, C₃ alkynyls, and C₂ alkynyls. A C₂-C₆alkynyl includes all moieties described above for C₂-C₅ alkynyls butalso includes C₆ alkynyls. A C₂-C₁₀ alkynyl includes all moietiesdescribed above for C₂-C₅ alkynyls and C₂-C₆ alkynyls, but also includesC₇, C₈, C₉ and C₁₀ alkynyls. Similarly, a C₂-C₁₂ alkynyl includes allthe foregoing moieties, but also includes C₁₁ and C₁₂ alkynyls.Non-limiting examples of C₂-C₁₂ alkenyl include ethynyl, propynyl,butynyl, pentynyl and the like. Unless stated otherwise specifically inthe specification, an alkyl group can be optionally substituted.

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain radical, having from two to twelve carbonatoms, and having one or more carbon-carbon triple bonds. Non-limitingexamples of C₂-C₁₂ alkynylene include ethynylene, propargylene and thelike. The alkynylene chain is attached to the rest of the moleculethrough a single bond and to the radical group through a single bond.The points of attachment of the alkynylene chain to the rest of themolecule and to the radical group can be through one carbon or any twocarbons within the chain. Unless stated otherwise specifically in thespecification, an alkynylene chain can be optionally substituted.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl, alkenyl or alknyl radical as defined above containing one totwelve carbon atoms. Unless stated otherwise specifically in thespecification, an alkoxy group can be optionally substituted.

“Alkylamino” refers to a radical of the formula —NHR_(a) or —NR_(a)R_(a)where each R_(a) is, independently, an alkyl, alkenyl or alkynyl radicalas defined above containing one to twelve carbon atoms. Unless statedotherwise specifically in the specification, an alkylamino group can beoptionally substituted.

“Alkylcarbonyl” refers to the —C(═O)R_(a) moiety, wherein R_(a) is analkyl, alkenyl or alkynyl radical as defined above. A non-limitingexample of an alkyl carbonyl is the methyl carbonyl (“acetal”) moiety.Alkylcarbonyl groups can also be referred to as “Cw-Cz acyl” where w andz depicts the range of the number of carbon in R_(a), as defined above.For example, “C1-C₁₀ acyl” refers to alkylcarbonyl group as definedabove, where R_(a) is C₁-C₁₀ alkyl, C₁-C₁₀ alkenyl, or C₁-C₁₀ alkynylradical as defined above. Unless stated otherwise specifically in thespecification, an alkyl carbonyl group can be optionally substituted.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical can be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which can include fused or bridgedring systems. Aryl radicals include, but are not limited to, arylradicals derived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, fluoranthene, fluorene,as-indacene, s-indacene, indane, indene, naphthalene, phenalene,phenanthrene, pleiadene, pyrene, and triphenylene. Unless statedotherwise specifically in the specification, the term “aryl” is meant toinclude aryl radicals that are optionally substituted.

“Aralkyl” refers to a radical of the formula —R_(b)—R_(c) where R_(b) isan alkylene, alkenylene or alkynylene group as defined above and R_(c)is one or more aryl radicals as defined above, for example, benzyl,diphenylmethyl and the like. Unless stated otherwise specifically in thespecification, an aralkyl group can be optionally substituted.

“Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a ringsstructure, wherein the atoms which form the ring are each carbon.Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring.Carbocyclic rings include aryls and cycloalkyl. cycloalkenyl andcycloalkynyl as defined herein. Unless stated otherwise specifically inthe specification, a carbocyclyl group can be optionally substituted.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclicfully saturated hydrocarbon radical consisting solely of carbon andhydrogen atoms, which can include fused or bridged ring systems, havingfrom three to twenty carbon atoms, preferably having from three to tencarbon atoms, and which is attached to the rest of the molecule by asingle bond. Monocyclic cycloalkyl radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic cycloalkyl radicals include, for example,adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl,and the like. Unless otherwise stated specifically in the specification,a cycloalkyl group can be optionally substituted.

“Cycloalkenyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,having one or more carbon-carbon double bonds, which can include fusedor bridged ring systems, having from three to twenty carbon atoms,preferably having from three to ten carbon atoms, and which is attachedto the rest of the molecule by a single bond. Monocyclic cycloalkenylradicals include, for example, cyclopentenyl, cyclohexenyl,cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenylradicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like.Unless otherwise stated specifically in the specification, acycloalkenyl group can be optionally substituted.

“Cycloalkynyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,having one or more carbon-carbon triple bonds, which can include fusedor bridged ring systems, having from three to twenty carbon atoms,preferably having from three to ten carbon atoms, and which is attachedto the rest of the molecule by a single bond. Monocyclic cycloalkynylradicals include, for example, cycloheptynyl, cyclooctynyl, and thelike. Unless otherwise stated specifically in the specification, acycloalkynyl group can be optionally substituted.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)—R_(d) whereR_(b) is an alkylene, alkenylene, or alkynylene group as defined aboveand R_(d) is a cycloalkyl, cycloalkenyl, cycloalkynyl radical as definedabove. Unless stated otherwise specifically in the specification, acycloalkylalkyl group can be optionally substituted.

“Chlorohydrin” refers to a radical having one of the following formulae:

“Protected chlorohydrin” refers to the above radical wherein thehydroxyl group is protected by a protecting group commonly known in theart to form, e.g., acetic acid ester (acetate), pivalic acid ester(pivalate) benzoid acid ester (benzoate), t-butyl ether, methoxymethylether, tetrahydropyranyl ether, allyl ether, benzyl ether,t-butyldimethylsilyl ether, t-butylphenylsilyl ether; (PG=protectinggroup):

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike. Unless stated otherwise specifically in the specification, ahaloalkyl group can be optionally substituted.

“Haloalkenyl” refers to an alkenyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless statedotherwise specifically in the specification, a haloalkenyl group can beoptionally substituted.

“Haloalkynyl” refers to an alkynyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,1-fluoropropynyl, 1-fluorobutynyl, and the like. Unless stated otherwisespecifically in the specification, a haloalkenyl group can be optionallysubstituted.

“Heterocyclyl,” “heterocyclic ring” or “heterocycle” refers to a stable3- to 20-membered non-aromatic ring radical which consists of two totwelve carbon atoms and from one to six heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur. Heterocyclycl orheterocyclic rings include heteroaryls as defined below. Unless statedotherwise specifically in the specification, the heterocyclyl radicalcan be a monocyclic, bicyclic, tricyclic or tetracyclic ring system,which can include fused or bridged ring systems; and the nitrogen,carbon or sulfur atoms in the heterocyclyl radical can be optionallyoxidized; the nitrogen atom can be optionally quaternized; and theheterocyclyl radical can be partially or fully saturated. Examples ofsuch heterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, a heterocyclyl group can be optionally substituted.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl radical to the rest of the molecule is through anitrogen atom in the heterocyclyl radical. Unless stated otherwisespecifically in the specification, a N-heterocyclyl group can beoptionally substituted.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)—R_(e)where R_(b) is an alkylene, alkenylene, or alkynylene chain as definedabove and R_(e) is a heterocyclyl radical as defined above, and if theheterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl canbe attached to the alkyl, alkenyl, alkynyl radical at the nitrogen atom.Unless stated otherwise specifically in the specification, aheterocyclylalkyl group can be optionally substituted.

“Heteroaryl” refers to a 5- to 20-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. For purposes of this invention,the heteroaryl radical can be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which can include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical can be optionally oxidized; the nitrogen atom can be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group can be optionallysubstituted.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. Unless stated otherwise specifically inthe specification, an N-heteroaryl group can be optionally substituted.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)—R_(f) whereR_(b) is an alkylene, alkenylene, or alkynylene chain as defined aboveand R_(f) is a heteroaryl radical as defined above. Unless statedotherwise specifically in the specification, a heteroarylalkyl group canbe optionally substituted.

“Thioalkyl” refers to a radical of the formula —SR_(a) where R_(a) is analkyl, alkenyl, or alkynyl radical as defined above containing one totwelve carbon atoms. Unless stated otherwise specifically in thespecification, a thioalkyl group can be optionally substituted.

The term “substituted” used herein means any of the above groups (i.e.,alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy,alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl,cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl,heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl,N-heteroaryl and/or heteroarylalkyl) wherein at least one hydrogen atomis replaced by a bond to a non-hydrogen atoms such as, but not limitedto: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groupssuch as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atomin groups such as thiol groups, thioalkyl groups, sulfone groups,sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such asamines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines,diarylamines, N-oxides, imides, and enamines; a silicon atom in groupssuch as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilylgroups, and triarylsilyl groups; and other heteroatoms in various othergroups. “Substituted” also means any of the above groups in which one ormore hydrogen atoms are replaced by a higher-order bond (e.g., a double-or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl,carboxyl, and ester groups; and nitrogen in groups such as imines,oximes, hydrazones, and nitriles. For example, “substituted” includesany of the above groups in which one or more hydrogen atoms are replacedwith NRgR_(h), NR_(g)C(═O)R_(h), NR_(g)C(═O)NR_(g)R_(h),NR_(g)C(═O)OR_(h), NR_(g)SO₂R_(h), OC(═O)NR_(g)R_(h), OR_(g), SR_(g),SORg, SO₂R_(g), OSO₂R_(g), SO₂OR_(g), ═NSO₂R_(g), and SO₂NR_(g)R_(h).“Substituted also means any of the above groups in which one or morehydrogen atoms are replaced with C(═O)R_(g), C(═O)OR_(g),C(═O)NR_(g)R_(h), CH₂SO₂R_(g), CH₂SO₂NR_(g)R_(h). In the foregoing,R_(g) and R_(h) are the same or different and independently hydrogen,alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl,cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl,haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.“Substituted” further means any of the above groups in which one or morehydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl,imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy,alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl,cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl,heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl,N-heteroaryl and/or heteroarylalkyl group. In addition, each of theforegoing substituents can also be optionally substituted with one ormore of the above substituents.

As used herein, the symbol

(hereinafter may be referred to as “a point of attachment bond”) denotesa bond that is a point of attachment between two chemical entities, oneof which is depicted as being attached to the point of attachment bondand the other of which is not depicted as being attached to the point ofattachment bond. For example,

indicates that the chemical entity “XY” is bonded to another chemicalentity via the point of attachment bond. Furthermore, the specific pointof attachment to the non-depicted chemical entity may be specified byinference. For example, the compound CH₃—R_(j), wherein R_(j) is H or

infers that when R_(j) is “XY”, the point of attachment bond is the samebond as the bond by which R_(j) is depicted as being bonded to CH₃.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the invention. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring may be replaced with anitrogen atom.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfrom, for example, the oxidation, reduction, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising administering a compound of thisinvention to a mammal for a period of time sufficient to yield ametabolic product thereof. Such products are typically identified byadministering a radiolabelled compound of the invention in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itsconversion products from the urine, blood or other biological samples.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

As used herein, a “subject” may be a human, non-human primate, mammal,rat, mouse, cow, horse, pig, sheep, goat, dog, cat and the like. Thesubject may be suspected of having or at risk for having a cancer, suchas prostate cancer, breast cancer, ovarian cancer, salivary glandcarcinoma, or endometrial cancer, or suspected of having or at risk forhaving acne, hirsutism, alopecia, benign prostatic hyperplasia, ovariancysts, polycystic ovary disease, precocious puberty, spinal and bulbarmuscular atrophy, or age-related macular degeneration. Diagnosticmethods for various cancers, such as prostate cancer, breast cancer,ovarian cancer, salivary gland carcinoma, or endometrial cancer, anddiagnostic methods for acne, hirsutism, alopecia, benign prostatichyperplasia, ovarian cysts, polycystic ovary disease, precociouspuberty, spinal and bulbar muscular atrophy, or age-related maculardegeneration and the clinical delineation of cancer, such as prostatecancer, breast cancer, ovarian cancer, salivary gland carcinoma, orendometrial cancer, diagnoses and the clinical delineation of acne,hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts,polycystic ovary disease, precocious puberty, spinal and bulbar muscularatrophy, or age-related macular degeneration are known to those ofordinary skill in the art.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets (e.g., cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“An “effective amount” refers to a therapeutically effective amount or aprophylactically effective amount. A “therapeutically effective amount”refers to an amount effective, at dosages and for periods of timenecessary, to achieve the desired therapeutic result, such as reducedtumor size, increased life span or increased life expectancy. Atherapeutically effective amount of a compound may vary according tofactors such as the disease state, age, sex, and weight of the subject,and the ability of the compound to elicit a desired response in thesubject. Dosage regimens may be adjusted to provide the optimumtherapeutic response. A therapeutically effective amount is also one inwhich any toxic or detrimental effects of the compound are outweighed bythe therapeutically beneficial effects. A “prophylactically effectiveamount” refers to an amount effective, at dosages and for periods oftime necessary, to achieve the desired prophylactic result, such assmaller tumors, increased life span, increased life expectancy orprevention of the progression of prostate cancer to acastration-resistant form. Typically, a prophylactic dose is used insubjects prior to or at an earlier stage of disease, so that aprophylactically effective amount may be less than a therapeuticallyeffective amount.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes:

-   -   (i) preventing the disease or condition from occurring in a        mammal, in particular, when such mammal is predisposed to the        condition but has not yet been diagnosed as having it;    -   (ii) inhibiting the disease or condition, i.e., arresting its        development;    -   (iii) relieving the disease or condition, i.e., causing        regression of the disease or condition; or    -   (iv) relieving the symptoms resulting from the disease or        condition, i.e., relieving pain without addressing the        underlying disease or condition. As used herein, the terms        “disease” and “condition” may be used interchangeably or may be        different in that the particular malady or condition may not        have a known causative agent (so that etiology has not yet been        worked out) and it is therefore not yet recognized as a disease        but only as an undesirable condition or syndrome, wherein a more        or less specific set of symptoms have been identified by        clinicians.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms whether or not they are specifically depicted herein. Opticallyactive (+) and (−), (R)- and (5)-, or (D)- and (L)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques, for example, chromatography and fractionalcrystallization. Conventional techniques for the preparation/isolationof individual enantiomers include chiral synthesis from a suitableoptically pure precursor or resolution of the racemate (or the racemateof a salt or derivative) using, for example, chiral high pressure liquidchromatography (HPLC). When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms are alsointended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system, using the ACD/NameVersion 9.07 software program, ChemDraw Ultra Version 11.0.1 and/orChemDraw Ultra Version 14.0 software naming program (CambridgeSoft). Forcomplex chemical names employed herein, a substituent group is namedbefore the group to which it attaches. For example, cyclopropylethylcomprises an ethyl backbone with cyclopropyl substituent. Except asdescribed below, all bonds are identified in the chemical structurediagrams herein, except for some carbon atoms, which are assumed to bebonded to sufficient hydrogen atoms to complete the valency.

II. Compounds and Pharmaceutical Compositions

As noted above, certain embodiments of the present invention aredirected to compounds useful for treatment of various cancers, includingvarious types of prostate cancers. While not wishing to be bound bytheory, it is believed that binding of the compounds to the androgenreceptor (for example at the N-terminal domain) may contribute to theactivity of the disclosed compounds. The compounds of the presentinvention relates to bisphenol ether compounds having a chlorohydrin ora protected chlorohydrin moiety which can impart improved properties tothe compounds compared to compounds lacking the chlorohydrin or aprotected chlorohydrin moiety (e.g., the right hand portion of acompound of of Formula I). For example, the improved properties includeimproved drug-like properties such as improved activity (e.g., androgenreceptor (AR) modulation), longer half-life (e.g., in vivo); decreasedtoxicity; better solubility, improved formulation, betterbioavailability, better pharmacokinetic profile; reduction in unwantedmetabolites and the like.

In one embodiment the invention includes compounds which can formcovalent bonds with the androgen receptor (AR) (e.g., at the N-terminaldomain), thus resulting in irreversible (or substantially irreversible)inhibition of the same. In this regard, the certain compounds of thepresent invention can be designed to include functional groups capableof forming covalent bonds with a nucleophile under certain in vivoconditions. For example, in some embodiments the reactivity of compoundsof the present invention is such that they will not substantially reactwith various nucleophiles (e.g., glutathione) when the compounds arefree in solution. However, when the free mobility of the compounds isrestricted, and an appropriate nucleophile is brought into closeproximity to the compound, for example when the compounds associatewith, or bind to, the androgen receptor, the compounds can be capable offorming covalent bonds with certain nucleophiles (e.g., thiols).

The present invention includes all compounds which can have the abovedescribed properties (i.e., binding to androgen receptor (AR)). In oneembodiment, the present invention is directed to a compound having astructure of Formula I:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein:

-   -   X is —O—, —S(O)₀₋₂, —C(═O)—, —C(OR⁵)₂—, —C(OR⁵)(OC(═O)R¹³)—,        —C(R³R⁴)—, —C(═CR³R⁴)—, —N(R⁵)—, —N(COR⁴)—, —CHNR⁵R⁶—,        —C(═NR⁵)—, —C(═NOR⁵)—, —C(═N—NHR⁷)—;    -   R¹ and R² are each independently H, halogen, C₁-C₁₀ alkyl,        C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, —OH, —OR⁵, —O(C₁-C₆)alkyl,        —OC(═O)R¹³, C₁-C₁₀ acyl, —S(O)₀₋₂R⁵, —NO₂, —CN, —NH₂, —NHR⁵,        —N(R⁵R⁶), —CO₂H, —CO₂R¹⁴, or —CONR⁵R⁶;    -   R³ and R⁴ are each independently H, halogen, —S(O)₀₋₂R¹⁴, C₁-C₁₀        alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl, aralkyl, C₁-C₁₀        acyl, or —NR⁵R⁶, or R³ and R⁴ may join to form a unsubstituted        or substituted mono-, bi-, or tri-cyclic carbocycle or        heterocycle containing from 3 to 20 carbon atoms;    -   R⁵ and R⁶ are each independently H, C₁-C₁₀ alkyl, C₂-C₁₀        alkenyl, or C₂-C₁₀ alkynyl;    -   R⁷ is each independently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀        alkynyl, aryl, aminocarbonyl, C₁-C₁₀ alkylcarbonyl, C₂-C₁₀        alkenylcarbonyl, C₂-C₁₀ alkynylcarbonyl, C₁-C₁₀        alkylaminocarbonyl, C₂-C₁₀ alkenylaminocarbonyl, or C₂-C₁₀        alkynylaminocarbonyl;    -   R¹³ is each independently C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, or        C₂-C₁₀ alkynyl;    -   R¹⁴ is each independently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, or aryl;    -   L¹ is hydroxyl or —OC(═O)R¹³;    -   L² and L³ are each independently H, halogen, hydroxyl,        —OC(═O)R¹³, —OC₁-C₁₀ alkyl, —OC₂-C₁₀ alkenyl, —OC₂-C₁₀ alkynyl,        —OR¹⁵, —SR⁵, —NR⁵R⁶, —O(C₁-C₁₀ acyl), —OC₁-C₁₀        alkylene-(—O—C₁-C₁₀ alkyl)_(p), —OC₁-C₁₀ alkylene-(—O—C₂-C₁₀        alkynyl)_(p), —OC₁-C₁₀ alkylene-(—O—C₂-C₁₀ alkenyl)_(p),        —OC₂-C₁₀ alkenylene-(—O—C₁-C₁₀ alkyl)_(p), —OC₂-C₁₀        alkenylene-(—O—C₂-C₁₀ alkenyl)_(p), —OC₂-C₁₀        alkenylene-(—O—C₂-C₁₀ alkynyl)_(p), —OC₂-C₁₀        alkynylene-(—O—C₁-C₁₀ alkyl)_(p), —OC₂-C₁₀ alkynylene-(—O—C₁-C₁₀        alkenyl)_(p), —OC₂-C₁₀ alkynylene-(—O—C₂-C₁₀ alkynyl)_(p),        carbocyclyl, aryl, heterocyclyl, or heteroaryl;    -   R¹⁵ is each independently selected from the group consisting of

-   -   wherein aa is a naturally occurring amino acid side chain and n        is an integer from 1 to 200; and    -   wherein each L² and L³ is optionally substituted with one or        more of halogen, hydroxyl, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkenyl, C₁-C₆ alkylene-C₁-C₆ alkoxy, C₂-C₆        alkenylene-C₁-C₆ alkoxy, C₂-C₆ alkynylene-C₁-C₆ alkoxy, C₁-C₆        alkylene-OH, C₂-C₆ alkenylene-OH, or C₂-C₆ alkynylene-OH;    -   a, b and c, are each independently 0, 1, 2, 3, 4, 5, or 6;    -   m and n are each independently 0, 1, 2, 3, or 4; and    -   p is 1, 2, 3, or 4.

Accordingly, certain embodiments of the present invention are directedto compounds that bind to the AR NTD. In some embodiment, compounds ofthe present invention can be useful for imaging of tumors with splicevariants using SPECT and/or methods of modulating AR NTD activity.

In various embodiments, different stereoisomers of the compound ofstructure (I) are provided, for example in some embodiments the compoundhas one of the following structures (Ia), (Ib), (Ic) or (Id):

In some embodiments, X is —O—. In other embodiments, X is —S(O)₀₋₂-. Insome embodiments, X is —C(═O)—. In one embodiment, X is —C(OR⁵)₂—. Inone embodiment, X is —C(OR⁵)(OC(═O)R¹³)—. In some embodiments, X is—C(R³R⁴)—. In some embodiments, X is —C(═CR³R⁴)—. In other embodiments,X is —N(R⁵)—. In one embodiment, X is —N(COR⁴)—. In one embodiment, X is—CHNR⁵R⁶—. In another embodiment, X is —C(═NR⁵)—. In some embodiments, Xis —C(═NOR⁵)—. In other embodiments, X is —C(═N—NHR⁷)—.

In some embodiments, X is —C(R³R⁴)— wherein R³ and R⁴ are eachindependently H or C₁-C₁₀ alkyl. In other embodiments, X is —C(R³R⁴)—wherein R³ and R⁴ are each independently C₁-C₁₀ alkyl. In someembodiments, X is —C(R³R⁴)— wherein R³ and R⁴ are each independentlyC₁-C₆ alkyl. In some embodiments, X is —C(R³R⁴)— wherein R³ and R⁴ areeach independently C₁-C₅ alkyl. In one embodiment, X is —C(R³R⁴)—wherein R³ and R⁴ are each independently C₁ alkyl. In anotherembodiment, X is —C(R³R⁴)— wherein R³ and R⁴ are each independently amethyl. In another embodiment, X is —C(R³R⁴)— wherein R³ and R⁴ are eachC₁ alkyl, wherein R³ and R⁴ are joined together to form a cyclopropylring.

In certain embodiments, R¹ is each independently H, halogen,—O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl, —C₁-C₁₀ alkyl,—C₂-C₁₀ alkenyl, —C₂-C₁₀ alkynyl, —OR⁵—CO₂H, —CO₂R¹⁴, or —CONR⁵R⁶. Incertain embodiments, R¹ is each independently H, halogen,—O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl, —C₁-C₁₀ alkyl,—C₂-C₁₀ alkenyl, —C₂-C₁₀ alkynyl, or —OR⁵. In another embodiment, R¹ iseach independently H or halogen.

In certain embodiments, R² is each independently H, halogen,—O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl, —C₁-C₁₀ alkyl,—C₂-C₁₀ alkenyl, —C₂-C₁₀ alkynyl, —OR⁵—CO₂H, -CO₂R¹⁴, or —CONR⁵R⁶. Incertain embodiments, R² is each independently H, halogen, H, halogen,—O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl, —C₁-C₁₀ alkyl,—C₂-C₁₀ alkenyl, —C₂-C₁₀ alkynyl, or —OR⁵. In another embodiment, R² iseach independently H or halogen.

In certain embodiments, R³ and R⁴ are each independently H, halogen,—S(O)₀₋₂R¹⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl, oraralkyl, C₁-C₁₀ acyl, or R³ and R⁴ may join to form a unsubstituted orsubstituted mono-, bi-, or tri-cyclic carbocycle or heterocyclecontaining from 3 to 20 carbon atoms.

In certain embodiments, R⁵ and R⁶ are each independently H, C₁-C₆ alkyl,C₂-C₆ alkenyl, or C₂-C₆ alkynyl. In some embodiments, when both R⁵ andR⁶ are present, R⁵ is H and R⁶ is C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆alkynyl.

In certain embodiments, R⁷ is each independently H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, or aryl.

In certain embodiments, R¹⁴ is each independently H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, or aryl.

In certain embodiments, R¹⁵ is each independently

In another embodiment, R¹⁵ is each independently

In some embodiments, R¹⁵ is each independently

In certain of the foregoing embodiments, L¹ is hydroxyl or —OC(═O)R¹³,wherein R¹³ is —C₁-C₁₀ alkyl, —C₂-C₁₀ alkenyl or —C₂-C₁₀ alkynyl. Insome embodiments, L¹ is hydroxyl. In another embodiment, L¹ is—OC(═O)C₁-C₆ alkyl. In one embodiment, L¹ is —OC(═O)C₁-C₃ alkyl. In someembodiments, L¹ is —OC(═O)CH₃.

In certain embodiments, L² and L³ are each independently H, halogen,hydroxyl, —OC(═O)R¹³, —OC₁-C₁₀ alkyl, —OC₂-C₁₀ alkenyl, —OC₂-C₁₀alkynyl, —OR¹⁵, —SR⁵, —NR⁵R⁶, —O(C₁-C₁₀ acyl), carbocyclyl, aryl,heterocyclyl, or heteroaryl. In some embodiments, L² and L³ are eachindependently H, halogen, hydroxyl, —OC(═O)R¹³, —OC₁-C₁₀ alkyl, —OC₂-C₁₀alkenyl, —OC₂-C₁₀ alkynyl, —OR¹⁵, —SR⁵, —NR⁵R⁶, or —O(C₁-C₁₀ acyl).

In certain of the foregoing embodiments, L² and L³ are eachindependently H, hydroxyl, —OC₁-C₁₀ alkyl, —C₂-C₁₀ alkenyl, —C₂-C₁₀alkynyl, or —OC(═O)R¹³, wherein R¹³ is -C₁-C₁₀ alkyl, —C₂-C₁₀ alkenyl or—C₂-C₁₀ alkynyl. In some embodiments, at least one of L² and L³ is ahydroxyl. In another embodiment, at least one of L² and L³ is a —OC₁-C₁₀alkyl or —OC(═O)C₁-C₁₀ alkyl. In a further embodiment, L² or L³ is ahydroxyl and the remainder is -OC₁-C₁₀ alkyl or —OC(═O)C₁-C₁₀ alkyl.

In another embodiment, at least one of L² and L³ is a carbocyclyl, aryl,heterocyclyl, or heteroaryl. In one embodiment, at least one of L² andL³ is heterocyclyl or heteroaryl. In some embodiment, at least one of L²and L³ is 3-7 membered heterocylyl, wherein said heteroaryl or saidheterocyclyl comprises at least one N atom in the ring.

In another embodiment, at least one of L² and L³ is selected from agroup consisting of pyrrole, furan, thiophene, pyrazole, pyridine,pyridazine, pyrimidine, imidazole, thiazole, isoxazole, oxadiazole,thiadiazole, oxazole, triazole, isothiazole, oxazine, triazine, azepine,pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazoline,pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine,piperazine, and tetrazine.

In one embodiment, n is 0, 1, or 2. In another embodiment, n is 0 or 1.

In one embodiment, m is 0, 1, or 2. In another embodiment, m is 0 or 1.

In some embodiment, a is 0, 1, 2, or 3. In another embodiment, a is 0,1, or 2. In one embodiment, a is 1.

In some embodiment, b is 0, 1, 2, or 3. In another embodiment, b is 0,1, or 2. In one embodiment, b is 1.

In some embodiment, c is 0, 1, 2, or 3. In another embodiment, c is 0,1, or 2. In one embodiment, c is 1.

In one embodiment, the compound of Formula I comprising one or morehalogens which can be radioactive isotopes of said halogens.

In some more specific embodiments of the compound of Formula I, thecompound has one of the following structures from Table 1, or apharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

TABLE 1 Representative Compounds No. Structure Name 1

3-(4-(2-(4-(2-chloro-3- hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol 1a

(R)-3-(4-(2-(4-((R)-2-chloro-3- hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol 1b

(S)-3-(4-(2-(4-((S)-2-chloro-3- hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol 1c

(R)-3-(4-(2-(4-((S)-2-chloro-3- hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol 1d

(S)-3-(4-(2-(4-((R)-2-chloro-3- hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol 2

3-(4-(2-(4-(3-acetoxy-2- chloropropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diyl diacetate 2a

(S)-3-(4-(2-(4-((S)-3-acetoxy-2- chloropropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diyl diacetate 2b

(R)-3-(4-(2-(4-((R)-3-acetoxy-2- chloropropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diyl diacetate 2c

(S)-3-(4-(2-(4-((R)-3-acetoxy-2- chloropropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diyl diacetate 2d

(R)-3-(4-(2-(4-((S)-3-acetoxy-2- chloropropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diyl diacetate

In one embodiment, the present invention is directed to a pharmaceuticalcomposition, comprising a compound having a structure of Formula I:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein:

-   -   X is —O—, —S(O)₀₋₂, —C(═O)—, —C(OR⁵)₂—, —C(OR⁵)(OC(═O)R¹³)—,        —C(R³R⁴)—, —C(═CR³R⁴)—, —N(R⁵)—, —N(COR⁴)—, —CHNR⁵R⁶—,        —C(═NR⁵)—, —C(═NOR⁵)—, —C(═N—NHR⁷)—;    -   R¹ and R² are each independently H, halogen, C₁-C₁₀ alkyl,        C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, —OH, —OR⁵, —O(C₁-C₆)alkyl,        —OC(═O)R¹³, C₁-C₁₀ acyl, —S(O)₀₋₂R⁵, —NO₂, —CN, —NH₂, —NHR⁵,        —N(R⁵R⁶), —CO₂H, CO₂R¹⁴, or CONR⁵R⁶;    -   R³ and R⁴ are each independently H, halogen, —S(O)₀₋₂R¹⁴, C₁-C₁₀        alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl, aralkyl, C₁-C₁₀        acyl, or —NR⁵R⁶, or R³ and R⁴ may join to form a unsubstituted        or substituted mono-, bi-, or tri-cyclic carbocycle or        heterocycle containing from 3 to 20 carbon atoms;    -   R⁵ and R⁶ is each independently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,        or C₂-C₁₀ alkynyl;    -   R⁷ is each independently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀        alkynyl, aryl, aminocarbonyl, C₁-C₁₀ alkylcarbonyl, C₂-C₁₀        alkenylcarbonyl, C₂-C₁₀ alkynylcarbonyl, C₁-C₁₀        alkylaminocarbonyl, C₂-C₁₀ alkenylaminocarbonyl, or C₂-C₁₀        alkynylaminocarbonyl;    -   R¹³ is each independently C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, or        C₂-C₁₀ alkynyl;    -   R¹⁴ is each independently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, or aryl;    -   L¹ is hydroxyl or —OC(═O)R¹³;    -   L² and L³ are each independently H, halogen, hydroxyl,        —OC(═O)R¹³, —OC₁-C₁₀ alkyl, —OC₂-C₁₀ alkenyl, —OC₂-C₁₀ alkynyl,        —OR¹⁵, —SR⁵, —NR⁵R⁶, —O(C₁-C₁₀ acyl), —OC₁-C₁₀        alkylene-(—O—C₁-C₁₀ alkyl)_(p), —OC₁-C₁₀ alkylene-(—O—C₂-C₁₀        alkynyl)_(p), —OC₁-C₁₀ alkylene-(—O—C₂-C₁₀ alkenyl)_(p),        —OC₂-C₁₀ alkenylene-(—O—C₁-C₁₀ alkyl)_(p), —OC₂-C₁₀        alkenylene-(—O—C₂—C₁₀ alkenyl)_(p), —OC₂-C₁₀        alkenylene-(—O—C₂-C₁₀ alkynyl)_(p), —OC₂-C₁₀        alkynylene-(—O—C₁-C₁₀ alkyl)_(p), —OC₂-C₁₀ alkynylene-(—O—C₁-C₁₀        alkenyl)_(p), —OC₂-C₁₀ alkynylene-(—O—C₂-C₁₀ alkynyl)_(p),        carbocyclyl, aryl, heterocyclyl, or heteroaryl;    -   R¹⁵ is each independently selected from the group consisting of

wherein aa is a naturally occurring amino acid side chain and n is aninteger from 1 to 200, and wherein each L² and L³ is optionallysubstituted with one or more of halogen, hydroxyl, C₁-C₆ alkoxy, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkenyl, C₁-C₆ alkylene-C₁-C₆ alkoxy, C₂-C₆alkenylene-C₁-C₆ alkoxy, C₂-C₆ alkynylene-C₁-C₆ alkoxy, C₁-C₆alkylene-OH, C₂-C₆ alkenylene-OH, or C₂-C₆ alkynylene-OH;

-   -   a, b and c, are each independently 0, 1, 2, 3, 4, 5, or 6;    -   m and n are each independently 0,1, 2, 3, or 4; and    -   p is 1, 2, 3, or 4.

In some embodiment, the pharmaceutical composition comprising a compoundhaving a structure of Formula I can further comprise a pharmaceuticallyacceptable carrier. In another embodiment, the pharmaceuticalcomposition comprising a compound having a structure of Formula I canfurther comprise an additional therapeutic agent. In one embodiment, thepharmaceutical composition comprising a compound having a structure ofFormula I can further comprise a pharmaceutically acceptable carrier andan additional therapeutic agent.

In another embodiment, the pharmaceutical composition comprising acompound having a structure of Formula I can further comprise anadditional therapeutic agent which is for treating prostate cancer,breast cancer, ovarian cancer, endometrial cancer, salivary glandcarcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarydisease, precocious puberty, spinal and bulbar muscular atrophy,age-related macular degeneration, or combinations thereof.

Accordingly, one embodiment comprises the use of the disclosed compoundsin combination therapy with one or more currently-used or experimentalpharmacological therapies which are utilized for treating the abovedisease states irrespective of the biological mechanism of action ofsuch pharmacological therapies, including without limitationpharmacological therapies which directly or indirectly inhibit theandrogen receptor, pharmacological therapies which are cyto-toxic innature, and pharmacological therapies which interfere with thebiological production or function of androgen (hereinafter, an“additional therapeutic agent”). By “combination therapy” is meant theadministration of any one or more of a compound of Formula I with one ormore of another therapeutic agent to the same patient such that theirpharmacological effects are contemporaneous with one another, or if notcontemporaneous, that their effects are synergistic with one anothereven though dosed sequentially rather than contemporaneously.

Such administration can include without limitation dosing of one or moreof a compound of Formula I and one or more of the additional therapeuticagent(s) as separate agents without any comingling prior to dosing, aswell as formulations which include one or more other androgen-blockingtherapeutic agents mixed with one or more compound of Formula I as apre-mixed formulation. Administration of the compound(s) of Formula I incombination with the additional therapeutic agents for treatment of theabove disease states can also include dosing by any dosing methodincluding without limitation, intravenous delivery, oral delivery,intra-peritoneal delivery, intra-muscular delivery, or intra-tumoraldelivery.

In another aspect of the present disclosure, the one or more of theadditional therapeutic agents can be administered to the patient beforeadministration of the compound(s) of Formula I. In another embodiment,the compound(s) of Formula I can be co-administered with one or more ofthe additional therapeutic agents. In yet another aspect, the one ormore additional therapeutic agents can be administered to the patientafter administration of the compound(s) of Formula I.

It is fully within the scope of the disclosure that the ratio of thedoses of compound(s) of Formula Ito that of the one or more additionaltherapeutic agents may or may not equal to one and can be variedaccordingly to achieve the optimal therapeutic benefit.

For greater clarity the compound(s) of Formula I that are combined withthe one or more additional therapeutic agents for improved treatment ofthe above disease states can comprise, but are not limited to anycompound having a structure of Formula I, including those compoundsshown in Table 1.

The additional therapeutic agents include without limitation anypharmacological agent which is currently approved by the FDA in the U.S.(or elsewhere by any other regulatory body) for use as pharmacologicaltreatment of any of the above disease states, or which is currentlybeing used experimentally as part of a clinical trial program thatrelates to the above disease states. Non-limiting examples of the otherpharmacological agents can comprise, without limitation: the chemicalentity known as ODM-201 (also known as BAY1841788) and relatedcompounds; which appears to bind to the AR and blocks its cellularfunction, and is currently in clinical development as a treatment forprostate cancer); the chemical entity known as enzalutamide(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide)and related compounds, which appears to be a blocker of the androgenreceptor (AR) LBD and a FDA-approved treatment for prostate cancer; thechemical entity known as Galeterone and related compounds which appearsto be a blocker of the androgen receptor (AR) LBD, and a CYP17 lyaseinhibitor, and also appears to decrease overall androgen receptor levelsin prostate cancer cells. Galeterone is currently in development as atreatment for prostate cancer; the chemical entity known as ARN-509(4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide)and related compounds which appears to be a blocker of the androgenreceptor (AR) LBD and is currently in development as a treatment forprostate cancer; the chemical entity known as abiraterone (or CB-7630;(3S,8R,9S,10R,13 S,14S)-10,13-dimethyl-17-(pyridin-3-yl)2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol),and related molecules, which appears to block the production of androgenand FDA-approved treatment for prostate cancer; the chemical entityknown as bicalutamide(N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide)and related compounds, which appears to be a blocker of the androgenreceptor (AR) LBD and which is currently used to treat prostate cancer,the chemical entity known as nilutamide(5,5-dimethyl-3-[4-nitro-3-(trifloromethyl)phenyl]imidazolidine-2,4-dione)and related compounds, which appears to be a blocker of the AR LBD andwhich is currently used to treat prostate cancer, the chemical entityknown as flutamide(2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide) and relatedcompounds, which appears to be a blocker of the androgen receptor (AR)LBD and which is currently used to treat prostate cancer, the chemicalentities known as cyproterone acetate(6-chloro-1β,2β-dihydro-17-hydroxy-3′H-cyclopropa[1,2]pregna-4,6-diene-3,20-dione)and related compounds, which appears to be a blocker of the androgenreceptor (AR) LBD and which is currently used to treat prostate cancer,the chemical entity known as docetaxel (Taxotere;1,7β,10β-trihydroxy-9-oxo-5β,20-epoxytax-11-ene-2α,4,13α-triyl 4-acetate2-benzoate 13-{(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate}) andrelated compounds, which appears to be a cytotoxic antimicrotubule agentand is currently used in combination with prednisone to treat prostatecancer, the chemical entity known as Bevacizumab (Avastin), a monoclonalantibody that recognizes and blocks vascular endothelial growth factor A(VEGF-A) and may be used to treat prostate cancer, the chemical entityknown as OSU-HDAC42((S)-(+)-N-hydroxy-4-(3-methyl-2-phenylbutyrylamino)-benzamide), andrelated compounds, which appears to act as a histone deacetylaseinhibitor, and is currently being developed as a treatment for prostatecancer, the chemical entity known as VITAXIN which appears to be amonoclonal antibody against the vascular integrin αvβ3 to preventangiogenesis, and which may be used to treat prostate cancer, thechemical entity known as sunitumib(N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide)and related compounds, which appears to inhibit multiple receptortyrosine kinases (RTKs) and may be used for treatment of prostatecancer, the chemical entity known as ZD-4054(N-(3-Methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridin-3-sulfonamid)and related compounds, which appears to block the edta receptor andwhich may be used for treatment of prostate cancer; the chemical entityknown as Cabazitaxel (XRP-6258), and related compounds, which appears tobe a cytotoxic microtubule inhibitor, and which is currently used totreat prostate cancer; the chemical entity known as MDX-010(Ipilimumab), a fully human monoclonal antibody that binds to and blocksthe activity of CTLA-4 which is currently in development as animmunotherapeutic agent for treatment of prostate cancer; the chemicalentity known as OGX 427 which appears to target HSP27 as an antisenseagent, and which is currently in development for treatment of prostatecancer; the chemical entity known as OGX 011 which appears to targetclusterin as an antisense agent, and which is currently in developmentas a treatment for prostate cancer; the chemical entity known asfinasteride (Proscar, Propecia;N-(1,1-dimethylethyl)-3-oxo-(5α,17β)-4-azaandrost-1-ene-17-carboxamide),and related compounds, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone, and may be used to treatprostate cancer; the chemical entity known as dutasteride (Avodart;5α,17β)-N-{2,5bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide)and related molecules, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone, and may be used in thetreatment of prostate cancer; the chemical entity known as turosteride((4aR,4bS,6aS,7S,9aS,9bS,11aR)-1,4a,6a-trimethyl-2-oxo-N-(propan-2-yl)-N-(propan-2ylcarbamoyl)hexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide),and related molecules, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone and may be used in thetreatment of prostate cancer; the chemical entity known as bexlosteride(LY-191,704;(4aS,10bR)-8-chloro-4-methyl-1,2,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one),and related compounds, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone and may be used in thetreatment of prostate cancer; the chemical entity known as izonsteride(LY-320,236;(4aR,10bR)-8-[(4-ethyl-1,3-benzothiazol-2-yl)sulfanyl]-4,10b-dimethyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one)and related compounds, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone and may be used for thetreatment of prostate cancer; the chemical entity known as FCE 28260 andrelated compounds, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone and may be used for thetreatment of prostate cancer; the chemical entity known as SKF105,111,and related compounds, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone and may be used for treatmentof prostate cancer.

Accordingly, in some embodiments, the pharmaceutical compositioncomprising a compound having a structure of Formula I can furthercomprise an additional therapeutic agent selected form the groupconsisting of enzalutamide, Galeterone, ARN-509; abiraterone,bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel,Bevacizumab (Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054,Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX 011,finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE28260, SKF105,111, ODM-201, radium 233, or related compounds thereof.

In some embodiments, compounds of Formula I which result in unstablestructures and/or unsatisfied valences are not included within the scopeof the invention.

In another embodiment, the present disclosure provides a pharmaceuticalcomposition comprising any of the foregoing compounds of Formula I and apharmaceutically acceptable carrier.

Compounds as described herein may be in the free form or in the form ofa salt thereof. In some embodiments, compounds as described herein maybe in the form of a pharmaceutically acceptable salt, which are known inthe art (Berge et al., J. Pharm. Sci. 1977, 66, 1). Pharmaceuticallyacceptable salt as used herein includes, for example, salts that havethe desired pharmacological activity of the parent compound (salts whichretain the biological effectiveness and/or properties of the parentcompound and which are not biologically and/or otherwise undesirable).Compounds as described herein having one or more functional groupscapable of forming a salt may be, for example, formed as apharmaceutically acceptable salt. Compounds containing one or more basicfunctional groups may be capable of forming a pharmaceuticallyacceptable salt with, for example, a pharmaceutically acceptable organicor inorganic acid. Pharmaceutically acceptable salts may be derivedfrom, for example, and without limitation, acetic acid, adipic acid,alginic acid, aspartic acid, ascorbic acid, benzoic acid,benzenesulfonic acid, butyric acid, cinnamic acid, citric acid,camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid,diethylacetic acid, digluconic acid, dodecylsulfonic acid,ethanesulfonic acid, formic acid, fumaric acid, glucoheptanoic acid,gluconic acid, glycerophosphoric acid, glycolic acid, hemisulfonic acid,heptanoic acid, hexanoic acid, hydrochloric acid, hydrobromic acid,hydriodic acid, 2-hydroxyethanesulfonic acid, isonicotinic acid, lacticacid, malic acid, maleic acid, malonic acid, mandelic acid,methanesulfonic acid, 2-napthalenesulfonic acid, naphthalenedisulphonicacid, p-toluenesulfonic acid, nicotinic acid, nitric acid, oxalic acid,pamoic acid, pectinic acid, 3-phenylpropionic acid, phosphoric acid,picric acid, pimelic acid, pivalic acid, propionic acid, pyruvic acid,salicylic acid, succinic acid, sulfuric acid, sulfamic acid, tartaricacid, thiocyanic acid or undecanoic acid. Compounds containing one ormore acidic functional groups may be capable of forming pharmaceuticallyacceptable salts with a pharmaceutically acceptable base, for example,and without limitation, inorganic bases based on alkaline metals oralkaline earth metals or organic bases such as primary amine compounds,secondary amine compounds, tertiary amine compounds, quaternary aminecompounds, substituted amines, naturally occurring substituted amines,cyclic amines or basic ion-exchange resins. Pharmaceutically acceptablesalts may be derived from, for example, and without limitation, ahydroxide, carbonate, or bicarbonate of a pharmaceutically acceptablemetal cation such as ammonium, sodium, potassium, lithium, calcium,magnesium, iron, zinc, copper, manganese or aluminum, ammonia,benzathine, meglumine, methylamine, dimethylamine, trimethylamine,ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine,tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine,glucamine, methylglucamine, theobromine, purines, piperazine,piperidine, procaine, N-ethylpiperidine, theobromine,tetramethylammonium compounds, tetraethylammonium compounds, pyridine,N,N-dimethylaniline, N-methylpiperidine, morpholine, N-methylmorpholine,N-ethylmorpholine, dicyclohexylamine, dibenzylamine,N,N-dibenzylphenethylamine, 1-ephenamine, N,N′-dibenzylethylenediamineor polyamine resins. In some embodiments, compounds as described hereinmay contain both acidic and basic groups and may be in the form of innersalts or zwitterions, for example, and without limitation, betaines.Salts as described herein may be prepared by conventional processesknown to a person skilled in the art, for example, and withoutlimitation, by reacting the free form with an organic acid or inorganicacid or base, or by anion exchange or cation exchange from other salts.Those skilled in the art will appreciate that preparation of salts mayoccur in situ during isolation and purification of the compounds orpreparation of salts may occur by separately reacting an isolated andpurified compound.

In some embodiments, compounds and all different forms thereof (e.g.free forms, salts, polymorphs, isomeric forms) as described herein maybe in the solvent addition form, for example, solvates. Solvates containeither stoichiometric or non-stoichiometric amounts of a solvent inphysical association the compound or salt thereof. The solvent may be,for example, and without limitation, a pharmaceutically acceptablesolvent. For example, hydrates are formed when the solvent is water oralcoholates are formed when the solvent is an alcohol.

In some embodiments, compounds and all different forms thereof (e.g.free forms, salts, solvates, isomeric forms) as described herein mayinclude crystalline and amorphous forms, for example, polymorphs,pseudopolymorphs, conformational polymorphs, amorphous forms, or acombination thereof. Polymorphs include different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, infrared spectra,melting points, density, hardness, crystal shape, optical and electricalproperties, stability and/or solubility. Those skilled in the art willappreciate that various factors including recrystallization solvent,rate of crystallization and storage temperature may cause a singlecrystal form to dominate.

In some embodiments, compounds and all different forms thereof (e.g.free forms, salts, solvates, polymorphs) as described herein includeisomers such as geometrical isomers, optical isomers based on asymmetriccarbon, stereoisomers, tautomers, individual enantiomers, individualdiastereomers, racemates, diastereomeric mixtures and combinationsthereof, and are not limited by the description of the formulaillustrated for the sake of convenience.

III. Methods

The present compounds find use in any number of methods. For example, insome embodiments the compounds can be useful in methods for modulatingandrogen receptor (AR). Accordingly, in one embodiment, the presentdisclosure provides the use of any one of the foregoing compounds ofFormula I for modulating androgen receptor (AR) activity. For example insome embodiments, modulating androgen receptor (AR) activity can be in amammalian cell. Modulating androgen receptor (AR) may be in a subject inneed thereof (e.g., a mammalian subject) and for treatment of any of thedescribed conditions or diseases.

In other embodiments, modulating androgen receptor (AR) activity can befor treatment of at least one indication selected from the groupconsisting of: prostate cancer, breast cancer, ovarian cancer,endometrial cancer, salivary gland carcinoma, hair loss, acne,hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty,spinal and bulbar muscular atrophy, age related macular degeneration,and combinations thereof. For example in some embodiments, theindication is prostate cancer. In other embodiments, the prostate canceris castration resistant prostate cancer (also referred to as hormonerefractory, androgen-independent, androgen deprivation resistant,androgen ablation resistant, androgen depletion-independent,castration-recurrent, anti-androgen-recurrent). While in otherembodiments, the prostate cancer is androgen dependent prostate cancer.In other embodiments, the spinal and bulbar muscular atrophy isKennedy's disease.

In some embodiments, compounds as described herein may be administeredto a subject. In one embodiment, the present invention can be directedto a method of treating castration resistant prostate cancer comprisingadministering a pharmaceutical composition comprising a compound havinga structure of Formula I. In some embodiments, the present invention canbe directed to a method of treating androgen-dependent prostate cancercomprising administering a pharmaceutical composition comprising acompound having a structure of Formula I. In other embodiments, thepresent invention can be directed to a method of treatingandrogen-independent prostate cancer comprising administering apharmaceutical composition comprising a compound having a structure ofFormula I.

In other embodiments, the present disclosure provides a method ofmodulating androgen receptor (AR) activity, the method comprisingadministering any one of the foregoing compounds of Formula I,pharmaceutically acceptable salt thereof, or pharmaceutical compositionof Formula I as described herein (including compositions comprising acompound of Formula I and an additional therapeutic agent), to a subject(e.g., mammal) in need thereof. In some embodiments, modulating androgenreceptor (AR) activity can be in a mammalian cell. In other embodiments,modulating androgen receptor (AR) activity can be in a mammal. In oneembodiment, modulating androgen receptor (AR) activity can be in ahuman.

The modulating androgen receptor (AR) activity may be for inhibiting ARN-terminal domain activity. The modulating androgen receptor (AR)activity may be for inhibiting androgen receptor (AR) activity. Themodulating may be in vivo. The modulating androgen receptor (AR)activity may be for treatment of at least one indication selected fromthe group consisting of: prostate cancer, breast cancer, ovarian cancer,endometrial cancer, salivary gland carcinoma, hair loss, acne,hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty,spinal and bulbar muscular atrophy (e.g., Kennedy's disease), and agerelated macular degeneration. The indication may be prostate cancer. Theprostate cancer may be castration-resistant prostate cancer. Theprostate cancer may be androgen dependent prostate cancer.

In accordance with another embodiment, there is provided a use of thecompounds of Formula I, pharmaceutically acceptable salt thereof, orpharmaceutical composition of Formula I as described herein forpreparation of a medicament for modulating androgen receptor (AR).

Alternatively, in one embodiment, the method of modulating androgenreceptor activity, comprising administering Formula I, pharmaceuticallyacceptable salt thereof, or pharmaceutical composition of Formula I asdescribed herein, are provided. In some embodiments, the administrationmay be to a mammal. In other embodiments, the administering may be to amammal in need thereof and in an effective amount for the treatment ofat least one indication selected from the group consisting of: prostatecancer, breast cancer, ovarian cancer, endometrial cancer, salivarygland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycysticovary disease, precocious puberty, spinal and bulbar muscular atrophy(e.g., Kennedy's disease), age related macular degeneration, andcombinations thereof.

Androgen ablation therapy causes a temporary reduction in prostatecancer tumor burden, but the malignancy will begin to grow again in theabsence of testicular androgens to form castrate resistant prostatecancer (CRPC). A rising titer of serum prostate-specific antigen (PSA)after androgen ablation therapy indicates biochemical failure, theemergence of CRPC, and re-initiation of an androgen receptor (AR)transcription program. Most patients succumb to CRPC within two years ofbiochemical failure.

AR is a transcription factor and a validated target for prostate cancertherapy. Current therapies include androgen ablation and administrationof antiandrogens. Most CRPC is suspected to be AR-dependent. AR hasdistinct functional domains that include the C-terminus ligand-bindingdomain (LBD), a DNA-binding domain (DBD), and an amino-terminal domain(NTD). AR NTD contains the activation function-1 (AF-1) that contributesmost of the activity to the AR. Recently, splice variants of the AR thatlack the LBD have been reported in prostate cancer cell lines (VCaP and22Rv1), and in CRPC tissues. To date more than 20 splice variants of ARhave been detected. Splice variants V7 and V567es are clinicallyrelevant with levels of expression correlated to poor survival and CRPC.AR V567es is solely expressed in 20% of metastases. Abirateroneresistance is associated with expression of AR splice variants.Enzalutamide also increases levels of expression of these constitutivelyactive AR splice variants. These splice variants lack LBD and therebywould not be inhibited by current therapies that target the AR LBD suchas antiandrogens or androgen ablation therapy. A single patient withadvanced prostate cancer can have many lesions throughout the body andskeleton and each tumor can have differing levels of expression of AR.

In some embodiments, the compounds as described herein orpharmaceutically acceptable salts thereof can find use in the diagnosticof at least one indication selected from the group consisting of:prostate cancer, breast cancer, ovarian cancer, endometrial cancer,salivary gland carcinoma, benign prostatic hyperplasia, hair loss, acne,hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty,spinal and bulbar muscular atrophy, and age-related maculardegeneration. In some embodiments, the compounds as described herein oracceptable salts thereof above can be used in the preparation of amedicament or a composition for imaging the prostate, for example forimaging benign prostate conditions or for imaging prostate cancer in asubject in need of such imaging (for example for diagnosis and/orlocation of prostate tumors).

In some embodiments, pharmaceutical compositions useful in modulatingandrogen receptor (AR) activity, in accordance with this invention maycomprise a salt of such a compound, preferably a pharmaceutically orphysiologically acceptable salt. Pharmaceutical preparations cantypically comprise one or more carriers, excipients or diluentsacceptable for the mode of administration of the preparation, be it byinjection, inhalation, topical administration, lavage, or other modessuitable for the selected treatment. Suitable carriers, excipients ordiluents are those known in the art for use in such modes ofadministration.

Suitable pharmaceutical compositions may be formulated by means known inthe art and their mode of administration and dose determined by theskilled practitioner. For parenteral administration, a compound may bedissolved in sterile water or saline or a pharmaceutically acceptablevehicle used for administration of non-water soluble compounds such asthose used for vitamin K. For enteral administration, the compound maybe administered in a tablet, capsule or dissolved in liquid form. Thetablet or capsule may be enteric coated, or in a formulation forsustained release. Many suitable formulations are known, including,polymeric or protein microparticles encapsulating a compound to bereleased, ointments, pastes, gels, hydrogels, or solutions which can beused topically or locally to administer a compound. A sustained releasepatch or implant may be employed to provide release over a prolongedperiod of time. Many techniques known to one of skill in the art aredescribed in Remington: the Science & Practice of Pharmacy by AlfonsoGennaro, 20^(th) ed., Lippencott Williams & Wilkins, (2000).Formulations for parenteral administration may, for example, containexcipients, polyalkylene glycols such as polyethylene glycol, oils ofvegetable origin, or hydrogenated naphthalenes. Biocompatible,biodegradable lactide polymer, lactide/glycolide copolymer, orpolyoxyethylene-polyoxypropylene copolymers may be used to control therelease of the compounds. Other potentially useful parenteral deliverysystems for modulatory compounds include ethylene-vinyl acetatecopolymer particles, osmotic pumps, implantable infusion systems, andliposomes. Formulations for inhalation may contain excipients, forexample, lactose, or may be aqueous solutions containing, for example,polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may beoily solutions for administration in the form of nasal drops, or as agel.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a compound as described herein, and an additionaltherapeutic agent and/or a pharmaceutically acceptable carrier. In someembodiments, the additional therapeutic agent can be for treatingprostate cancer, breast cancer, ovarian cancer, endometrial cancer,salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts,polycystic ovary disease, precocious puberty, spinal and bulbar muscularatrophy or age related macular degeneration. In other embodiments, theadditional therapeutic agent can be enzalutamide, galeterone, ARN-509,ODN-201 abiraterone, bicalutamide, nilutamide, flutamide, cyproteroneacetate, docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXIN,sunitumib, ZD-4054, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX427, OGX 011, finasteride, dutasteride, turosteride, bexlosteride,izonsteride, FCE 28260, SKF105,111 ODM-201, or related compoundsthereof.

Compounds described herein may also be used in assays and for researchpurposes. Definitions used include ligand dependent activation of theandrogen receptor (AR) by androgens such as dihydrotestosterone (DHT) orthe synthetic androgen (R1881) used for research purposes.Ligand-independent activation of the androgen receptor (AR) refers totransactivation of the full length androgen receptor (AR) in the absenceof androgen (ligand) by, for example, stimulation of the cAMP dependentprotein kinase (PKA) pathway with forskolin (FSK). Some compounds andcompositions of this invention may inhibit both FSK and androgen (e.g.R1881, a synthetic androgen) induction of ARE luciferase (ARE-luc).Constituative activity of the androgen receptor (AR) refers to splicevariants lacking the androgen receptor (AR) ligand-binding domain. Suchcompounds may block a mechanism that is common to both ligand dependentand ligand independent activation of the androgen receptor (AR), as wellas constitutively active splice variants of the androgen receptor (AR)that lack ligand-binding domain. This could involve any step inactivation of the androgen receptor (AR) including dissociation ofheatshock proteins, essential posttranslational modifications (e.g.,acetylation, phosphorylation), nuclear translocation, protein-proteininteractions, formation of the transcriptional complex, release of corepressors, and/or increased degradation. Some compounds andcompositions of this invention may inhibit ligand-only activity and mayinterfere with a mechanism specific to ligand dependent activation(e.g., accessibility of the ligand binding domain (LBD) to androgen).Numerous disorders in addition to prostate cancer involve the androgenaxis (e.g., acne, hirsutism, alopecia, benign prostatic hyperplasia) andcompounds interfering with this mechanism may be used to treat suchconditions. Some compounds and compositions of this invention may onlyinhibit FSK induction and may be specific inhibitors to ligandindependent activation of the androgen receptor (AR). These compoundsand compositions may interfere with the cascade of events that normallyoccur with FSK and/or PKA activity or any downstream effects that mayplay a role on the androgen receptor (AR) (e.g. FSK increases MAPKactivity which has a potent effect on androgen receptor (AR) activity).Examples may include an inhibitor of cAMP and or PKA or other kinases.Some compounds and compositions of this invention may induce basallevels of activity of the AR (no androgen or stimulation of the PKApathway). Some compounds and compositions of this invention may increaseinduction by R1881 or FSK. Such compounds and compositions may stimulatetranscription or transactivation of the AR. Some compounds andcompositions of this invention may inhibit activity of the androgenreceptor. Interleukin 6 (IL 6) also causes ligand independent activationof the androgen receptor (AR) in LNCaP cells and can be used in additionto FSK.

Compounds or pharmaceutical compositions in accordance with thisinvention or for use in this invention may be administered by means of amedical device or appliance such as an implant, graft, prosthesis,stent, etc. Also, implants may be devised which are intended to containand release such compounds or compositions. An example would be animplant made of a polymeric material adapted to release the compoundover a period of time.

It is to be noted that dosage values may vary with the exact imagingprotocol. For any particular subject, specific dosage regimens may beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the compositions. Dosage ranges set forth herein are exemplary onlyand do not limit the dosage ranges that may be selected by medicalpractitioners. The amount of active compound(s) in the composition mayvary according to factors such as the disease state, age, sex, andweight of the subject. Dosage regimens can be adjusted to provide theoptimum imaging result. For example, a single bolus can be administered,several divided doses can be administered over time or the dose can beproportionally reduced or increased as indicated by the imaging results.It can be advantageous to formulate parenteral compositions in dosageunit form for ease of administration and uniformity of dosage.

In general, compounds of the invention should be used without causingsubstantial toxicity. Toxicity of the compounds of the invention can bedetermined using standard techniques, for example, by testing in cellcultures or experimental animals and determining the therapeutic index,i.e., the ratio between the LD50 (the dose lethal to 50% of thepopulation) and the LD100 (the dose lethal to 100% of the population).In some circumstances, such as in severe disease conditions, substantialexcesses of the compositions may be administered for therapeuticeffects. Some compounds of this invention may be toxic at someconcentrations. Titration studies may be used to determine toxic andnon-toxic concentrations. Toxicity may be evaluated by examining aparticular compound's or composition's specificity across cell linesusing PC3 or DU145 cells as possible negative controls since these cellsdo not express functional AR. Animal studies may be used to provide anindication if the compound has any effects on other tissues. Systemictherapy that targets the AR will not likely cause major problems toother tissues since antiandrogens and androgen insensitivity syndromeare not fatal.

Compounds for use in the present invention may be obtained from medicalsources or modified using known methodologies from naturally occurringcompounds. In addition, methods of preparing or synthesizing compoundsof the present invention will be understood by a person of skill in theart having reference to known chemical synthesis principles. Forexample, Auzou et al 1974 European Journal of Medicinal Chemistry 9(5),548-554 describes suitable synthetic procedures that may be consideredand suitably adapted for preparing compounds of any one of the compoundsof structure (I) as set out above. Other references that may be helpfulinclude: Debasish Das, Jyh-Fu Lee and Soofin Cheng “Sulfonic acidfunctionalized mesoporous MCM-41 silica as a convenient catalyst forBisphenol-A synthesis” Chemical Communications, (2001) 2178-2179; U.S.Pat. No. 2,571,217 Davis, Orris L.; Knight, Horace S.; Skinner, John R.(Shell Development Co.) “Halohydrin ethers of phenols.” (1951); andRokicki, G.; Pawlicki, J.; Kuran, W. “Reactions of4-chloromethyl-1,3-dioxolan-2-one with phenols as a new route to polyolsand cyclic carbonates.” Journal fuer Praktische Chemie (Leipzig) (1985)327, 718-722.

In some embodiments, compounds and all different forms thereof asdescribed herein may be used, for example, and without limitation, incombination with other treatment methods for at least one indicationselected from the group consisting of: prostate cancer, breast cancer,ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss,acne, hirsutism, ovarian cysts, polycystic ovary disease, precociouspuberty, spinal and bulbar muscular atrophy, and age related maculardegeneration. For example, compounds and all their different forms asdescribed herein may be used as neoadjuvant (prior), adjunctive(during), and/or adjuvant (after) therapy with surgery, radiation(brachytherapy or external beam), or other therapies (eg. HIFU), and incombination with chemotherapies, androgen ablation, antiandrogens or anyother therapeutic approach.

In an exemplary embodiment for imaging the prostate, a dose of thedisclosed compounds in solution (typically 5 to 10 millicuries or 200 to400 MBq) can be typically injected rapidly into a saline drip runninginto a vein, in a patient. Then, the patient is placed in the SPECT fora series of one or more scans which may take from 20 minutes to as longas an hour (often, only about one quarter of the body length may beimaged at a time). Methods for SPECT scanning are well known in the art.

The compounds described herein may be used for in vivo or in vitroresearch uses (i.e. non-clinical) to investigate the mechanisms oforphan and nuclear receptors (including steroid receptors such asandrogen receptor (AR)). Furthermore, these compounds may be usedindividually or as part of a kit for in vivo or in vitro research toinvestigate signal transduction pathways and/or the activation of orphanand nuclear receptors using recombinant proteins, cells maintained inculture, and/or animal models.

EXAMPLES

All non-aqueous reactions were performed in flame-dried round bottomedflasks. The flasks were fitted with rubber septa and reactions wereconducted under a positive pressure of argon unless otherwise specified.Stainless steel syringes were used to transfer air- andmoisture-sensitive liquids. Flash column chromatography was performed asdescribed by Still et al. (Still, W. C.; Kahn, M.; Mitra, A. J. Org.Chem. 1978, 43, 2923) using 230-400 mesh silica gel. Thin-layerchromatography was performed using aluminum plates pre-coated with 0.25mm 230-400 mesh silica gel impregnated with a fluorescent indicator (254nm). Thin-layer chromatography plates were visualized by exposure toultraviolet light and a “Seebach” staining solution (700 mL water, 10.5g Cerium (IV) sulphate tetrahydrate, 15.0 g molybdato phosphoric acid,17.5 g sulphuric acid) followed by heating (˜1 min) with a heating gun(˜250° C.). Organic solutions were concentrated on Büchi R-114 rotatoryevaporators at reduced pressure (15-30 torr, house vacuum) at 25-40° C.

Commercial regents and solvents were used as received. All solvents usedfor extraction and chromatography were HPLC grade. Normal-phase Si gelSep paks™ were purchased from waters, Inc. Thin-layer chromatographyplates were Kieselgel 60F₂₅₄. All synthetic reagents were purchased fromSigma Aldrich and Fisher Scientific Canada.

Example 1 Synthesis of(R)-3-(4-(2-(4-((R)-2-chloro-3-hydroxypropoxy)phenyl)propan-2-yl)phenoxypropane-1,2-diol(1a)

Compound i

To a stirred solution of(S)-4-(2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenol(1 equiv) in ethanol at rt was added NEt₃ (1 equiv) and(S)-oxiran-2-ylmethanol (3 equiv), then the reaction mixture wasrefluxed. After the completion of the reaction, the product wasextracted with ethyl acetate (×3). The organic layer was washed withdeionized water, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel to provide(R)-3-(4-(2-(4-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol.See FIGS. 4A-4B for NMR spectra.

Compound ii

To a mixture of(R)-3-(4-(2-(4-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol(1 equiv) and trityl chloride, pyridine and DMAP were added. Thereaction mixture was heated to 50° C. After the completion of thereaction, the product was extracted with ethyl acetate (×3). The organiclayer was washed with deionized water, dried over anhydrous magnesiumsulfate, filtered, and concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography on silicagel to provide(S)-1-(4-(2-(4-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)-3-(triphenyl-l4-oxidanyl)propan-2-ol.See FIGS. 3A-3B for NMR spectra.

Compound iii

To a solution of(S)-1-(4-(2-(4-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)-3-(triphenyl-l4-oxidanyl)propan-2-ol(1 equiv) in carbon tetrachloride, PPh₃ was added and the reactionmixture was refluxed. After the completion of the reaction, the productwas extracted with ethyl acetate (×3). The organic layer was washed withdeionized water, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel to provide(S)-4-((4-(2-(4-((S)-2-chloro-3-(triphenyl-l4-oxidanyl)propoxy)phenyl)propan-2-yl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxolane.See FIG. 2 for NMR spectrum.

Compound 1a

To a solution of(S)-4-((4-(2-(4-((S)-2-chloro-3-(triphenyl-l4-oxidanyl)propoxy)phenyl)propan-2-yl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxolane(1 equiv) in methanol, HCl was added and the reaction was stirred at rt.After the completion of the reaction, the product was extracted withethyl acetate (×3). The organic layer was washed with deionized water,dried over anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The resulting residue was purified by flash columnchromatography on silica gel to provide Compound 1a. See FIG. 1A-1B forNMR spectra of Compound 1a.

Example 2 Synthesis of(R)-3-(4-(2-(4((S)-2-chloro-3-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol(1c) Compound 1c

Compound 1c was synthesized according to Example 1 but starting with(R)-oxiran-2-ylmethanol instead of (S)-oxiran-2ylmethanol. See FIG.5A-5B for NMR spectra of Compound 1c.

Example 3 Compound Activity

LNCaP cells were transiently transfected with PSA (6.1 kb)-luciferasefor 24 h prior to pre-treatment with compounds of the invention (e.g.,Compound 1c) ranging in concentration from 62.5 ng/ml to 1.5 ug/ml for 1hour before the addition of vehicle, or synthetic androgen, R1881 (1 nM)to induce luciferase production. After 24 h of incubation with R1881,the cells were harvested, and relative luciferase activities weredetermined. To determine the IC₅₀, treatments were normalized to thepredicted maximal activity induction (in the absence of test compounds,vehicle only).

TABLE 2 IC₅₀ values for selected compounds (μM) Compound Trial 1 Trial 2Trial 3 Trial 4 Average IC₅₀ 1c 14.01 19.38 17.00 15.83 16.69 ± 2.68

One skilled in the art will recognize that variations to the order ofthe steps and reagents discussed in the Examples are possible.

In addition, protecting group strategies may be employed for preparationof the compounds disclosed herein. Such strategies are well known tothose of skill in the art. Exemplary protecting groups and relatedstrategies are disclosed in Greene's Protective Groups in OrganicSynthesis, Wiley-Interscience; 4 edition (Oct. 30, 2006), which ishereby incorporated by reference in its entirety. In certainembodiments, a protecting group is used to mask an alcohol moiety whileperforming other chemical transformations. After removal of theprotecting group, the free hydroxyl is obtained. Such protecting groupsand strategies are well known in the art.

Although various embodiments of the invention are disclosed herein, manyadaptations and modifications may be made within the scope of theinvention in accordance with the common general knowledge of thoseskilled in this art. Such modifications include the substitution ofknown equivalents for any aspect of the invention in order to achievethe same result in substantially the same way. Numeric ranges areinclusive of the numbers defining the range. The word “comprising” isused herein as an open-ended term, substantially equivalent to thephrase “including, but not limited to”, and the word “comprises” has acorresponding meaning. As used herein, the singular forms “a”, “an” and“the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “a thing” includes more thanone such thing. Citation of references herein is not an admission thatsuch references are prior art to the present invention. Any prioritydocument(s) and all publications, including but not limited to patentsand patent applications, cited in this specification are incorporatedherein by reference as if each individual publication were specificallyand individually indicated to be incorporated by reference herein and asthough fully set forth herein. The invention includes all embodimentsand variations substantially as hereinbefore described and withreference to the examples and drawings.

1. A compound having a structure of Formula (I):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein: X is —O—, —S(O)₀₋₂, —C(═O)—, —C(OR⁵)₂—, —C(OR⁵)(OC(═O)R¹³)—,—C(R³R⁴)—, —C(═CR³R⁴)—, —N(R⁵)—, —N(COR⁴)—, —CHNR⁵R⁶—, —C(═NR⁵)—,—C(═NOR⁵)—, —C(═N—NHR⁷)—; R¹ and R² are each independently H, halogen,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, —OH, —OR⁵, —O(C₁-C₆)alkyl,—OC(═O)R¹³, C₁-C₁₀ acyl, —S(O)₀₋₂R⁵, —NO₂, —CN, —NH₂, —NHR⁵, —N(R⁵R⁶),—CO₂H, CO₂R¹⁴, or CONR⁵R⁶; R³ and R⁴ are each independently H, halogen,—S(O)₀₋₂R¹⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂C₁₀ alkynyl, aryl, aralkyl,C₁-C₁₀ acyl, or —NR⁵R⁶, or R³ and R⁴ may join to form a unsubstituted orsubstituted mono-, bi-, or tri-cyclic carbocycle or heterocyclecontaining from 3 to 20 carbon atoms; R⁵ and R⁶ is each independently H,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ alkynyl; R⁷ is eachindependently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl,aminocarbonyl, C₁-C₁₀ alkylcarbonyl, C₂-C₁₀ alkenylcarbonyl, C₂-C₁₀alkynylcarbonyl, C₁-C₁₀ alkylaminocarbonyl, C₂-C₁₀ alkenylaminocarbonyl,or C₂-C₁₀ alkynylaminocarbonyl; R¹³ is each independently C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, or C₂-C₁₀ alkynyl; R¹⁴ is each independently H, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, or aryl; L¹ is hydroxyl or—OC(═O)R¹³; L² and L³ are each independently H, halogen, hydroxyl,—OC(═O)R¹³, —OC₁-C₁₀ alkyl, —OC₂-C₁₀ alkenyl, —OC₂-C₁₀ alkynyl, —OR¹⁵,—SR⁵, —NR⁵R⁶, —O(C₁-C₁₀ acyl), —OC₁-C₁₀ alkylene-(—O—C₁-C₁₀ alkyl)_(p),—OC₁-C₁₀ alkylene-(—O—C₂-C₁₀ alkynyl)_(p), —OC₁-C₁₀ alkylene-(—O—C₂-C₁₀alkenyl)_(p), —OC₂-C₁₀ alkenylene-(—O—C₁-C₁₀ alkyl)_(p), —OC₂-C₁₀alkenylene-(—O—C₂-C₁₀ alkenyl)_(p), —OC₂-C₁₀ alkenylene-(—O—C₂-C₁₀alkynyl)_(p), —OC₂-C₁₀ alkynylene-(—O—C₁-C₁₀ alkyl)_(p), —OC₂-C₁₀alkynylene-(—O—C₁-C₁₀ alkenyl)_(p), —OC₂-C₁₀ alkynylene-(—O—C₂-C₁₀alkynyl)_(p), carbocyclyl, aryl, heterocyclyl, or heteroaryl; wherein atleast one of L² and L³ is substituted or unsubstituted carbocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted heteroaryl; R¹⁵ is eachindependently selected from the group consisting of

wherein aa is a naturally occurring amino acid side chain and n is aninteger from 1 to 200; and a, b and c, are each independently 0, 1, 2,3, 4, 5, or 6; m and n are each independently 0,1, 2, 3, or 4; and p is1, 2, 3, or
 4. 2. The compound of claim 1, wherein R¹ and R² are eachindependently H, —CN, or halogen.
 3. The compound of claim 1, wherein Xis —C(R³R⁴)—.
 4. (canceled)
 5. The compound of claim 1, wherein R³ andR⁴ are each methyl.
 6. (canceled)
 7. The compound of claim 1, wherein R⁵is H or C₁-C₁₀ alkyl.
 8. The compound of claim 1, wherein L¹ is hydroxylor —OC(═O)CH₃.
 9. (canceled)
 10. The compound of claim 1, wherein atleast one of L² and L³ is substituted or unsubstituted group selectedfrom a pyrrole, furan, thiophene, pyrazole, pyridine, pyridazine,pyrimidine, imidazole, thiazole, isoxazole, oxadiazole, thiadiazole,oxazole, triazole, isothiazole, triazine, tetrazine, oxazine, azepine,pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazoline,pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine,or piperazine.
 11. The compound of claim 1, wherein a is 0 or
 1. 12. Thecompound of claim 1, wherein b is 0 or
 1. 13. The compound of claim 1,wherein c is 0 or
 1. 14. The compound of claim 1, wherein the compoundhas one of the following structures (Ia), (Ib), (Ic) or (Id):


15. (canceled)
 16. A pharmaceutical composition, comprising: apharmaceutically acceptable carrier and a compound of formula (I):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein: X is —O—, —S(O)₀₋₂, —C(═O)—, —C(OR⁵)₂—, —C(OR⁵)(OC(═O)R¹³)—,—C(R³R⁴)—, —C(═CR³R⁴)—, —N(R⁵)—, —N(COR⁴)—, —CHNR⁵R⁶—, —C(═NR⁵)—,—C(═NOR⁵)—, —C(═N—NHR⁷)—; R¹ and R² are each independently H, halogen,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, —OH, —OR⁵, —O(C₁-C₆)alkyl,—OC(═O)R¹³, C₁-C₁₀ acyl, —S(O)₀₋₂R⁵, —NO₂, —CN, —NH₂, —NHR⁵, —N(R⁵R⁶),—CO₂H, CO₂R¹⁴, or CONR⁵R⁶; R³ and R⁴ are each independently H, halogen,—S(O)₀₋₂R¹⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂C₁₀ alkynyl, aryl, aralkyl,C₁-C₁₀ acyl, or —NR⁵R⁶, or R³ and R⁴ may join to form a unsubstituted orsubstituted mono-, bi-, or tri-cyclic carbocycle or heterocyclecontaining from 3 to 20 carbon atoms; R⁵ and R⁶ is each independently H,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ alkynyl; R⁷ is eachindependently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl,aminocarbonyl, C₁-C₁₀ alkylcarbonyl, C₂-C₁₀ alkenylcarbonyl, C₂-C₁₀alkynylcarbonyl, C₁-C₁₀ alkylaminocarbonyl, C₂-C₁₀ alkenylaminocarbonyl,or C₂-C₁₀ alkynylaminocarbonyl; R¹³ is each independently C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, or C₂-C₁₀ alkynyl; R¹⁴ is each independently H, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, or aryl; L¹ is hydroxyl or—OC(═O)R¹³; L² and L³ are each independently H, halogen, hydroxyl,—OC(═O)R¹³, —OC₁-C₁₀ alkyl, —OC₂-C₁₀ alkenyl, —OC₂-C₁₀ alkynyl, —OR¹⁵,—SR⁵, —NR⁵R⁶, —O(C₁-C₁₀ acyl), —OC₁-C₁₀ alkylene-(—O—C₁-C₁₀ alkyl)_(p),—OC₁-C₁₀ alkylene-(—O—C₂-C₁₀ alkynyl)_(p), —OC₁-C₁₀ alkylene-(—O—C₂-C₁₀alkenyl)_(p), —OC₂-C₁₀ alkenylene-(—O—C₁-C₁₀ alkyl)_(p), —OC₂-C₁₀alkenylene-(—O—C₂-C₁₀ alkenyl)_(p), —OC₂-C₁₀ alkenylene-(—O—C₂-C₁₀alkynyl)_(p), —OC₂-C₁₀ alkynylene-(—O—C₁-C₁₀ alkyl)_(p), —OC₂-C₁₀alkynylene-(—O—C₁-C₁₀ alkenyl)_(p), —OC₂-C₁₀ alkynylene-(—O—C₂-C₁₀alkynyl)_(p), carbocyclyl, aryl, heterocyclyl, or heteroaryl; wherein atleast one of L² and L³ is substituted or unsubstituted carbocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted heteroaryl; R¹⁵ is eachindependently selected from the group consisting of

wherein aa is a naturally occurring amino acid side chain and n is aninteger from 1 to 200; and a, b and c, are each independently 0, 1, 2,3, 4, 5, or 6; m and n are each independently 0,1, 2, 3, or 4; and p is1, 2, 3, or
 4. 17. (canceled)
 18. The pharmaceutical composition ofclaim 16, further comprising a pharmaceutically acceptable carrier andan additional therapeutic agent.
 19. The pharmaceutical composition ofclaim 18, wherein the additional therapeutic agent is for treatingprostate cancer, breast cancer, ovarian cancer, endometrial cancer,salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts,polycystic ovary disease, precocious puberty, spinal and bulbar muscularatrophy, age-related macular degeneration, or combinations thereof. 20.The pharmaceutical composition of claim 18, wherein the additionaltherapeutic agent is enzalutamide, Galeterone, ARN-509; abiraterone,bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel,Bevacizumab (Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054,Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX 011,finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE28260, SKF105,111, ODM-201, radium 233, or related compounds thereof.21. A method for modulating androgen receptor activity, comprising:administering a pharmaceutical composition according to claim 16 to apatient in need thereof.
 22. A method for treating a condition ordisease that is responsive to modulation of androgen receptor activity,comprising: administering a pharmaceutical composition according toclaim 16 to a patient in need thereof, wherein said condition or diseaseis selected from the group consisting of: prostate cancer, breastcancer, ovarian cancer, endometrial cancer, salivary gland carcinoma,hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease,precocious puberty, spinal and bulbar muscular atrophy, and age-relatedmacular degeneration.
 23. The method of claim 22, wherein the conditionor disease is prostate cancer.
 24. The method of claim 22, wherein thecondition or disease is castration resistant prostate cancer.
 25. Themethod of claim 22, wherein the condition or disease isandrogen-dependent prostate cancer.
 26. A method for treating acondition or disease selected from the group consisting of: prostatecancer, breast cancer, ovarian cancer, endometrial cancer, salivarygland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycysticovary disease, precocious puberty, spinal and bulbar muscular atrophy,and age-related macular degeneration, comprising: administering to apatient in need thereof a compound having the following structure (I):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein: X is —O—, —S(O)₀₋₂, —C(═O)—, —C(OR⁵)₂—, —C(OR⁵)(OC(═O)R¹³)—,—C(R³R⁴)—, —C(═CR³R⁴)—, —N(R⁵)—, —N(COR⁴)—, —CHNR⁵R⁶—, —C(═NR⁵)—,—C(═NOR⁵)—, —C(═N—NHR⁷)—; R¹ and R² are each independently H, halogen,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, —OH, —OR⁵, —O(C₁-C₆)alkyl,—OC(═O)R¹³, C₁-C₁₀ acyl, —S(O)₀₋₂R⁵, —NO₂, —CN, —NH₂, —NHR⁵, —N(R⁵R⁶),—CO₂H, CO₂R¹⁴, or CONR⁵R⁶; R³ and R⁴ are each independently H, halogen,—S(O)₀₋₂R¹⁴, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂C₁₀ alkynyl, aryl, aralkyl,C₁-C₁₀ acyl, or —NR⁵R⁶, or R³ and R⁴ may join to form a unsubstituted orsubstituted mono-, bi-, or tri-cyclic carbocycle or heterocyclecontaining from 3 to 20 carbon atoms; R⁵ and R⁶ is each independently H,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, or C₂-C₁₀ alkynyl; R⁷ is eachindependently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, aryl,aminocarbonyl, C₁-C₁₀ alkylcarbonyl, C₂-C₁₀ alkenylcarbonyl, C₂-C₁₀alkynylcarbonyl, C₁-C₁₀ alkylaminocarbonyl, C₂-C₁₀ alkenylaminocarbonyl,or C₂-C₁₀ alkynylaminocarbonyl; R¹³ is each independently C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, or C₂-C₁₀ alkynyl; R¹⁴ is each independently H, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, or aryl; L¹ is hydroxyl or—OC(═O)R¹³; L² and L³ are each independently H, halogen, hydroxyl,—OC(═O)R¹³, —OC₁-C₁₀ alkyl, —OC₂-C₁₀ alkenyl, —OC₂-C₁₀ alkynyl, —OR¹⁵,—SR⁵, —NR⁵R⁶, —O(C₁-C₁₀ acyl), —OC₁-C₁₀ alkylene-(—O—C₁-C₁₀ alkyl)_(p),—OC₁-C₁₀ alkylene-(—O—C₂-C₁₀ alkynyl)_(p), —OC₁-C₁₀ alkylene-(—O—C₂-C₁₀alkenyl)_(p), —OC₂-C₁₀ alkenylene-(—O—C₁-C₁₀ alkyl)_(p), —OC₂-C₁₀alkenylene-(—O—C₂-C₁₀ alkenyl)_(p), —OC₂-C₁₀ alkenylene-(—O—C₂-C₁₀alkynyl)_(p), —OC₂-C₁₀ alkynylene-(—O—C₁-C₁₀ alkyl)_(p), —OC₂-C₁₀alkynylene-(—O—C₁-C₁₀ alkenyl)_(p), —OC₂-C₁₀ alkynylene-(—O—C₂-C₁₀alkynyl)_(p), carbocyclyl, aryl, heterocyclyl, or heteroaryl; wherein atleast one of L² and L³ is substituted or unsubstituted carbocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted heteroaryl; R¹⁵ is eachindependently selected from the group consisting of

wherein aa is a naturally occurring amino acid side chain and n is aninteger from 1 to 200; and a, b and c, are each independently 0, 1, 2,3, 4, 5, or 6; m and n are each independently 0,1, 2, 3, or 4; and p is1, 2, 3, or
 4. 27. The method of claim 26, wherein the condition ordisease is prostate cancer.
 28. The method of claim 26, wherein thecondition or disease is castration resistant prostate cancer orandrogen-dependent prostate cancer.
 29. The compound of claim 1, whereinL² is H and L³ is substituted or unsubstituted carbocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heterocyclyl, orsubstituted or unsubstituted heteroaryl.
 30. The compound of claim 1,wherein at least one of L² and L³ is carbocyclyl, aryl, heterocyclyl, orheteroaryl, each substituted with halogen, cyano, nitro, oxo,alkyl,alkenyl, alkynyl, alkoxy, alkylamino, alkylcarbonyl, thioalkyl,cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, —NR_(g)R_(h),—NR_(g)C(═O)R_(h), —NR_(g)C(═O)NR_(g)R_(h), —NR_(g)C(═O)OR_(h),—NR_(g)SO₂R_(h), —OC(═O)NR_(g)R_(h), —OR_(g), —SR_(g), —SOR_(g),—SO₂R_(g), —OSO₂R_(g), —SO₂OR_(g), —SO₂NR_(g)R_(h), —C(═O)R_(g),—C(═O)OR_(g), —C(═O)NR_(g)R_(h), —CH₂SO₂R_(g), or —CH₂SO₂—NR_(g)R_(h),wherein R_(g) and R_(h) are each hydrogen, alkyl, or haloalkyl.
 31. Thecompound of claim 1, wherein at least one of L² and L³ is carbocyclyl,aryl, heterocyclyl, or heteroaryl, each substituted with NR_(g)SO₂R_(h)or SO₂R_(g), wherein R_(g) and R_(h) are each hydrogen or alkyl.